The present invention relates to hydrazide compounds with angiogenic activity. In particular, the present invention relates to angiogenic water-soluble, biodegradable polymers having a terminal hydrazide group on one or both end optionally linking the polymer to a residue of a naturally-occurring alpha-L-amino acid or a dipeptide thereof. The present invention also relates to polymer networks cross-linked via the hydrazide-terminal polymers of the invention, and to the use of the hydrazide compounds and polymer networks of the present invention to promote angiogenesis.
Synthetic, degradable polymers are currently being evaluated as medical implants in a wide range of applications, such as orthopedic bone fixation devices, drug delivery systems, cardiovascular implants, and scaffolds for the regeneration of tissue. Blood vessels are a pre-requisite to a functional, implanted tissue engineered device and implanted devices often fail to be incorporated into body tissue due to insufficient angiogenesis, that is, lack of formation of new blood vessels from a pre-existing vascular bed, which provides the necessary blood supply to the implant.
Attempts have been made to improve the level of angiogenesis in implanted tissue regeneration scaffolds by the use of biological molecules such as angiogenesis promoters, cytokines, and growth factors. While often effective, these biological compounds are expensive and not fully characterized with regard to their toxicity. Angiogenesis is a complex and highly biologically regulated process involving a coordinated sequence of endothelial cell division, degradation of vascular basement membrane and surrounding extracellular matrix with migration of endothelial cells. Under normal conditions angiogenesis is seen in the female reproductive system and wound healing whereas abnormal angiogenesis may contribute to tumor neovascularization, psoriasis, endometriosis or arthritis. In tissue engineering, angiogenesis is crucial to encourage cellular growth into a tissue regeneration scaffold and to ensure the development of functional tissue within the scaffold by providing adequate nutrients and oxygen to the device.
Several strategies have been employed to induce vascularization of a scaffold by incorporating biological moieties including growth factors, or the use of tumorigenic cell lines that will secrete angiogenic substances. U.S. Pat. No. 6,261,585 discloses angiogenic polymeric material that is not inherently angiogenic but rather attracts growth factors to the site of implantation.
Hydrogels are polymeric materials which swell in water without dissolution. Because of their compliance with soft tissue in terms of mechanical properties and high water content, hydrogels have been investigated for use in a wide range of medical applications such as drug delivery systems, contact lenses, surface coatings for blood-contacting materials and wound care products. In the field of tissue engineering, hydrogels have been investigated for the repair of skin, bone, cartilage, tendon and nerves. Both hydrogels obtained from natural materials such as alginate and collagen, and synthetic hydrogels obtained by crosslinking polymers such as poly(ethylene glycol) have been used. In contrast to hydrogels derived from natural materials, synthetic hydrogels often provide greater control over properties such as gelling time, crosslink density, compressive modulus and degradation rate. Biodegradable hydrogels for tissue regeneration are required which resorb over time without the release of toxic degradation products.
Preparation of hydrogels typically requires hydrophilic polymers such as poly(ethylene oxide), block copolymers of poly (ethylene oxide-co-propylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), polyamines, polyaminoamides, polypeptides, polysaccharides, cellulosics such as carboxymethylcellulose and hydroxyethylcellulose, chondroitin sulfate, heparin, alginates, proteins such as collagen or gelatin, and other polymers well known in the art, which are typically crosslinked by ionic or covalent linkages. For example, hydrogels may be formed from polysaccharides crosslinked by monovalent or multivalent cations such as sodium or calcium. Polyethylene oxide-polypropylene glycol block copolymers may be crosslinked by hydrogen bonding. Polyelectrolytes may be crosslinked in aqueous solutions by monvalent or multivalent ions or polyelectrolytes of the opposite charge to form highly swollen hydrogels. The ionic crosslinking groups include phenyls, amines, imines, amides, carboxylic acids, sulfonic acids and phosphate groups. Hydrogels may be prepared from precursors polymers such as soluble polyamines that are covalently crosslinked with a water-soluble diisothiocyanate such as polyethylene glycol diisothiocyanate. Polymers with ethylenically unsaturated groups may be crosslinked by free radical reactions typically employing a radical initiator. For example, poly ethylene glycol acrylates may be polymerized using photoinitiators that generate free radicals on exposure to ultraviolet or visible light.
Diphenols are monomeric starting materials for polycarbonates, polyiminocarbonates, polyarylates, polyurethanes, and the like. Commonly owned U.S. Pat. Nos. 5,099,060 and 5,198,507 disclose amino acid-derived diphenyl compounds useful in the polymerization of polycarbonates and polyiminocarbonates. The resulting polymers are useful as degradable polymers in general and as tissue-compatible, bioerodible materials for medical uses, in particular. The suitability of these polymers for their end use application is the result of their polymerization from diphenols derived from the naturally occurring amino acid, L-tyrosine. The disclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are hereby incorporated by reference. These previously-known polymers are strong, water-insoluble materials.
The same monomeric L-tyrosine derived diphenols are also used in the synthesis of polyarylates as described in commonly owned U.S. Pat. No. 5,216,115 and in the synthesis of poly(alkylene oxide) block copolymers with the aforementioned polycarbonates and polyarylates, which is disclosed in commonly owned U.S. Pat. No. 5,658,995. The disclosures of U.S. Pat. Nos. 5,216,115 and 5,658,995 are also hereby incorporated by reference.
Commonly owned U.S. Pat. No. 6,284,862 discloses dihydroxy monomers prepared from hydroxy acid amides of L-tyrosine that are also useful starting materials in the polymerization of polycarbonates, polyarylates, and the like. The preparation of polycarbonates and polyarylates from these monomers is also disclosed. The disclosure of U.S. Pat. No. 6,284,862 is also hereby incorporated by reference.
The foregoing monomers can be used to polymerize essentially any polymer capable of being derived from a diphenyl or a dihydroxy monomer, such as polyethers, polyphosphazines and the like.
There remains a need for a means by which the level of angiogenesis in implanted tissue regeneration scaffolds formed from such polymers and monomers may be improved.